Oral Chinese patent medicines for acute myocardial infarction after percutaneous coronary intervention: A protocol for systematic review and network meta-analysis

Background: Acute myocardial infarction (AMI) is a serious and fatal heart disease with one of the highest mortality rates in the world. In some countries, percutaneous coronary intervention (PCI) is the preferred reperfusion strategy after AMI, but it cannot achieve safe and effective treatment of AMI after PCI remains a challenging clinical problem. The potential of oral Chinese patent medicines to treat AMI after PCI has been demonstrated, but which type of oral Chinese patent medicines may be preferred remains controversial. The aim of this network meta-analysis was to investigate the efficacy and safety of multiple oral Chinese patent medicines in the treatment of AMI after PCI. Methods: We will conduct a literature search from China National Knowledge Infrastructure, formerly Chinese Biomedical Database (SinoMed), Wanfang Data, Chongqing VIP, PubMed, Embase, Web of Science and Cochrane Library (The Cochrane Database of Systematic Reviews) from their inception until to November 1, 2022, with language restricted to Chinese and English. Then, the study selection process will follow the Preferred Reporting Items for Meta-Analyses guideline, and the quality assessment will be conducted with Cochrane Collaboration’s tool. Pairwise and network meta-analysis will be conducted using the WinBUGS V.1.4.3.37 and STATA V.13. Additionally, sensitivity analysis, subgroup analysis, quality assessment, Small-study effects and publication bias will be performed. Ethics and dissemination: This work is based on published research and therefore does not require ethical approval. This review will be published in peer-reviewed journals. PROSPERO registration number: CRD42020188065.


Introduction
Acute myocardial infarction (AMI) is caused by acute coronary artery occlusion and blood flow interruption, resulting in continuous ischemia and hypoxia of myocardial cells. It is a serious fatal heart disease, [1] one of the diseases with the highest mortality in the world, and a serious threat to human health and quality of life. [2] According to its pathophysiology, clinic and prognosis, it is usually divided into 5 types. [3] Generally speaking, coronary lumen stenosis is between 50% and 75%, and no symptoms of myocardial ischemia will occur in the quiet state. However, when the mood swings or under the stress state, hemodynamics will change, [4,5] the atheromatous plaque ruptured, platelet aggregation formed thrombosis, [6,7] and blood flow decreased or interrupted, resulting in myocardial infarction. [8] In recent years, due to the gradual improvement of secondary prevention of coronary heart disease, [9] the incidence and mortality of AMI have been decreasing. [10,11] However, appear easily AMI acute or subacute left ventricular free wall rupture, ventricular septal rupture, acute mitral insufficiency, right ventricular infarction, wall of left ventricular aneurysm formation, and complications such as heart failure, [12,13] and Medicine myocardial ischemia can seriously damage the systolic and diastolic function of the heart, [14] from fear and anxiety can excite sympathetic nerve, increase cardiac load, further exacerbate the disease. [15] Therefore, AMI should be treated immediately after onset, and actively prevent the occurrence of serious complications.
Recent studies have shown that the main mechanism of AMI initiation is plaque rupture or erosion accompanied by overburden thrombosis. [16] This process is mainly related to inflammatory response, vascular endothelial injury, platelet activation and aggregation and other factors. [17][18][19][20] Various clinical guidelines recommend a variety of treatment plans and drugs, and AMI should be mainly managed according to ALS algorithm (ABCDE). [21] Management of myocardial infarction focuses on hemodynamic stability, pain relief, reduction of myocardial oxygen consumption, increase of myocardial oxygen supply and initiation of antithrombotic therapy. [22] In countries with well-established percutaneous coronary intervention (PCI) networks and fast transmission times, PCI is the preferred reperfusion strategy. The European Society of Cardiology recommends the use of dual antiplatelet therapy after PCI, in which patients should take clopidogrel and aspirin for 9 to 12 months to reduce the incidence of major adverse cardiovascular events. [23] However, if the drug dose is maintained for a long time, there will still be 10% to 15% patients with myocardial infarction, stroke and death. [24,25] The incidence of "non-reflow" caused by reperfusion injury [26] ranges from 5% to 50%, [27,28] which may increase the size of myocardial infarction and affect the recovery of cardiac function, thus increasing the long-term end point events, leading to a large number of patients who cannot obtain satisfactory treatment response. [29] Therefore, although PCI can clear the stenosis of the obstructive heart and blood vessels and improve the symptoms of angina pectoris, it cannot change the etiology of coronary heart disease, and achieving safe and effective treatment of AMI after PCI remains a challenging clinical problem.
As one of the characteristics of traditional Chinese culture, traditional Chinese medicine (TCM) has emerged as early as 3000 years ago and has rich therapeutic experience. [30] Due to the lack of objective and quantitative evaluation criteria, TCM is regarded as complementary or alternative medicine in most western countries. Nowadays, TCM is becoming more and more popular in many developed and developing countries. [31] A study has shown that TCM can be used as a supplementary and alternative method for primary and secondary prevention of cardiovascular diseases. [32] Chinese patent medicine is an important part of TCM. Oral Chinese patent medicine is a general term of oral liquid dosage form (solution dosage form, suspension dosage form, emulsion dosage form) and oral solid dosage form (powder, capsule, tablet, pill). [33] At present, oral Chinese patent medicine has been widely used in the clinical treatment of AMI after PCI in East and Southeast Asia. [34,35] At present, there have been systematic reviews on the effectiveness and safety of single oral Chinese patent medicine in the treatment of AMI after PCI. [36,37] However, the increasing variety of oral Chinese patent medicines means that the comparison between the 2 oral Chinese patent medicines is more complicated. For patients with AMI after PCI, there is no relevant research to confirm whether different oral Chinese patent medicines have different efficacy, as well as which oral Chinese patent medicines have the best efficacy and safety. Therefore, it is also a challenge for clinicians to choose which oral Chinese patent medicine to use as the first-line treatment. Online meta-analysis can be used to directly and indirectly compare the efficacy and safety of different oral Chinese patent medicines in the treatment of AMI after PCI, and to rank them. Therefore, we decided to conduct a network meta-analysis to explore the relative effectiveness and safety of different oral Chinese patent medicines, and to provide evidence for their clinical application and precise positioning.

Objective
The objective of this systematic review and network meta-analysis is to compare the efficacy and safety of oral Chinese patent medicines for the treatment of AMI after PCI in the national essential medicines list of China.

Methods and analysis
The network meta-analysis protocol has been registered on the International Prospective Register of Systematic Review, the registration number is CRD 42020188065. Our protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guideline. [38]

Patient and public involvement
The network meta-analysis is a review and summary of previous research results, and therefore do not require the participation of patients and the public.

Study types.
We will include all relevant randomized controlled trials (RCTs), quasi-RCTs will be excluded, such as using in clinic order allocation of RCT, case report is not included.

Participants.
Patients (age ≥ 18 years) who were diagnosed with AMI according to any standard criteria (such as Heart Disease and Stroke Statis-2020 Update: A Report From the American Heart Association) and who received PCI were included. [39] Patients with serious fatal diseases would be excluded such as cancer.

Interventions.
Any oral Chinese patent medicine used to treat AMI after PCI can be interfered. Regardless of dosage, dosage form, course of treatment and manufacturer, and these proprietary Chinese medicines are used in combination with conventional treatment. The experimental group was treated with oral Chinese patent medicine combined routine, while the control group was treated with oral Chinese patent medicine combined routine treatment or simple routine treatment, and the routine treatment measures should be the same between different RCT. Thus eligible combination: oral Chinese patent medicine + routine treatment versus routine treatment and oral Chinese patent medicine + routine treatment versus another oral Chinese patent medicine + routine treatment.

Primary outcomes.
Primary outcomes included the rate of cardiovascular events and mortality.

Study selection process
EndNote X9 (Thomson Reuters, New York, NY) software will be used to manage the literature and perform filtering, and categorize the document and remove duplicates. After classifying the literature and removing duplicates, 2 independent reviewers (WZ and FJX) review the titles and abstracts of the identified studies to exclude irrelevant parts. Then 2 reviewers (WZ and FJX) will read the full text and finally determine the research suitable for network meta-analysis. During this process, if there is any disagreement or inconsistency between the 2 reviewers, ask a third researcher (SJJ) to help make a judgment. Figure 1 is a schematic diagram of literature selection in this study.

Data extraction
Two independent reviewers (FJX and YML) used Microsoft Excel to independently extract and manage the data. The extracted data items include: Before the formal data extraction, 10 studies were randomly selected to test and modify the pre-designed table. In the data extraction process, if there is any objection can be negotiated, or by a third reviewer (SJJ) accuracy and consistency checking of data.

Risk of bias assessment
According to the Cochrane Collaboration Risk of Bias Tool (http://handbook-5-1.cochrane.org/), 2 reviewers (SGF and XHL) independently assessed the risk of bias, which included the 7 specific domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome data, incomplete outcome data, selective reporting, and other bias. If necessary, will be the third reviewer (WZ) to solve different opinions.

Data synthesis
We will generate descriptive statistics for the trial, and study population characteristics across all eligible trials, describing the types of comparisons and some important variables, either clinical or methodological (such as year of publication, age, severity of illness, sponsorship and clinical setting). We will draw the network diagram to graphically present the available evidence.

Pairwise meta-analyses
For each direct treatment, more than 2 RCTs should be performed for paired meta-analyses to study the role of oral Chinese patent drugs in treatment by visually inspecting the forest plots. We will use the SMD as the effect measure for continuous outcome variables, and use odds ratio to evaluate the effect size of dichotomous variables. The heterogeneity of this analysis will be assessed by Cochrane χ 2 test and I 2 statistics, a fixed-effect model will be used to analyze the data if there is no heterogeneity (P ≥ .1, I 2 ≤ 50%). If there is evidence of heterogeneity (P < .1, I 2 > 50%), a random-effect model will be used, and the possible causes will be searched from both methodological and clinical. In this analysis, we also used the tool described in the Cochrane Collaboration Handbook (http://handbook-5-1. cochrane.org/) as a reference guide for assessing heterogeneity.

Network meta-analysis
Network element can compare multiple interventions at the same time, while retaining the internal randomization of individual trials. Therefore, we will use the network meta-analysis model for all studies within the Bayesian framework. Using a random effects network meta-analysis to analyze the primary and secondary outcomes, we will estimate all possible pairwise relative effects and rank the interventions for each oral Chinese patent medicine. For each outcome, the distribution of ranking probabilities and surface under the cumulative ranking curve are used to estimate the relative rank of different oral Chinese patent medicines. [40] In this study, WinBUGS V.1.4.3.37 and STATA V.13 will be used to analyze the data. [41] Report the results in standardized mean differences, along with 95% confidence interval (CI) based on 100,000 Monte Carlo simulations and vague priors. Model convergence will be assessed by examining trace and history plots and by calculating the Gelman-Rubin statistic. Systematic descriptions will be provided instead if the heterogeneity between studies is too great, especially if the clinical or methodological heterogeneity is too great to perform a meta-analysis.

Assumption of transitivity
We will evaluate the transitivity assumption by comparing the distribution of clinical and methodological variables that are considered as potential effect modifiers (e.g., changes in AMI severity, medication, coronary lumen status after PCI, attack frequency of angina pectoris or duration, mean baseline cardiac function grading and age) across oral Chinese patent medicines interventions. [42,43]

Assessment of inconsistency
Inconsistent including inconsistent cycle and design, is the same compare the difference between direct and indirect effect estimates. [44] We will use the node-splitting method to evaluate whether there is inconsistency between direct and indirect evidence for the same comparison, [45] and P > .05 indicates consistency. As far as we know, the effect of the inconsistency test is low. [46] Therefore, we need to be careful with inconsistent statistical inferences.

Subgroup and sensitivity analyses
We will explore the possible sources of significant inconsistency or heterogeneity by meta-regression analyses and subgroup. If data are sufficient, subgroup analyses will be performed in terms of age, sex ratio, cardiac function grade before PCI, comorbidities, duration of treatment, and study quality. It is well known that TCM research always involves the problem of syndrome differentiation and treatment. [47] The oral Chinese patent medicines in this study are mainly used to remove blood stasis, supplement Qi and nourish Yin, regulate Qi and expand chest to relieve pain. Therefore, we will perform subgroup analyses on different syndrome types. If more than 10 studies were available, we will perform meta-regression analyses. We will recalculate the summary effect by excluding studies one by one for sensitivity analyses, and observe the impact on the final results. [48] 3.13. Small-study effects and publication bias We will use a comparison-adjusted funnel plot to evaluate the comparison and result of each treatment for small-study effects. If the meta-analysis comprises ≥10 trials, a funnel plot will be used to assess publication bias. [49] Then use Egger's test to evaluate the asymmetry of the funnel plot.

Quality of evidence
Using GRADEprofiler (GRADEpro3.6software, The cochrane Collaboration, Britain), we will use the Grading of Recommendations Assessment, Development and Evaluation guidelines to assess the quality of evidence and strength of recommendations for the main outcomes. [50] The quality of evidence will be divided into 4 levels: very low, low, moderate and high. Study limitations (risk of bias), indirectness, inconsistency, publication bias, and inaccuracies can reduce the quality of evidence, whereas residual confounding, dose-response gradients, and large magnitude of effect can improve the quality of evidence.

Discussion
Although the primary prevention of coronary heart disease has improved, cardiovascular disease is still the main cause of human morbidity and death, and its prevalence has continued and rapidly increased in the past few decades, causing a huge social and economic burden worldwide. [51] PCI is the main method for the treatment of ST-elevation myocardial infarction in China. [52] However, although PCI can significantly alleviate the symptoms of AMI and reduce the incidence of complications after AMI, studies have shown that the mortality of patients with stent thrombosis within 30 days is about 20% to 45%, [53] indicating that there is still a risk of adverse cardiac events and even death after PCI. [54] The proposed network meta-analysis will provide evidence of the comparative safety and effectiveness of oral Chinese patent medicines for AMI after PCI on the national essential drugs list of China. By the network meta-analysis, we hope to provide clinicians with valuable evidence, while being able to aid decision-making for patients, as well as guide future studies. However, this study also has some limitations. The heterogeneity among studies may be high, which may impact the final results. We will publish the findings and results of this research in a peer-reviewed journal.